title: Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer.
abstract: Recognition of the pivotal role of estrogen in the aetiology of breast cancer has led to the development of antiestrogens (AE), such as tamoxifen (TAM) as effective therapies for the treatment and prevention of this disease. However, despite their widespread clinical efficacy, response to AEs is often short-lived, and acquired or innate therapeutic resistance remains a major obstacle in the successful treatment of breast cancer. Thus, delineating the intracellular pathways that mediate the cellular response to estrogen could potentially lead to new, more effective approaches to the treatment of breast cancer, particularly endocrine-resistant disease. Here, we have identified the BCL-2 homology 3 (BH3)-only, pro-apoptotic regulator, PUMA (p53 upregulated modulator of apoptosis) as an estrogen target gene that is acutely downregulated in response to estrogen in breast cancer cell lines, independently of their p53 status. PUMA is transcriptionally upregulated following treatment with TAM, and knock down of PUMA expression in these cells attenuates the apoptotic response to TAM. Furthermore, low PUMA expression in breast carcinomas is significantly associated with breast cancer-specific death (P=0.0014 and P=0.0115, for mRNA and protein, respectively), and worse outcome in TAM-treated patients (mRNA, P=1.49e-05). These findings suggest that the dysregulation of apoptotic signaling pathways such as those executed through PUMA, can significantly impact on both the progression and therapeutic responsiveness of breast cancer. Moreover, they provide a convincing rationale for exploring new therapeutic approaches involving endocrine and non-endocrine therapies that target apoptotic pathways as an effective strategy for tackling endocrine refractory disease.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: C G
authors.initials: CG
authors.lastname: Roberts
authors.forename: E K A
authors.initials: EK
authors.lastname: Millar
authors.forename: S A
authors.initials: SA
authors.lastname: O'Toole
authors.forename: C M
authors.initials: CM
authors.lastname: McNeil
authors.forename: G M
authors.initials: GM
authors.lastname: Lehrbach
authors.forename: M
authors.initials: M
authors.lastname: Pinese
authors.forename: P
authors.initials: P
authors.lastname: Tobelmann
authors.forename: R A
authors.initials: RA
authors.lastname: McCloy
authors.forename: E A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: R L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: A J
authors.initials: AJ
authors.lastname: Butt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D004965:Estrogen Antagonists; D004967:Estrogens; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol